Implantable medical device comprising a pro-healing poly(ester-amide)

ABSTRACT

The present invention relates to implantable medical devices, in particular stents, comprising pro-healing poly(ester-amide)s.

FIELD

This invention relates to organic chemistry, polymer chemistry,physiology, material science and medical devices.

BACKGROUND

Until the mid-1980s, the accepted treatment for atherosclerosis, i.e.,narrowing of the coronary artery(ies) was coronary by-pass surgery.While effective and evolved to a relatively high degree of safety forsuch an invasive procedure, by-pass surgery still involves potentiallyserious complications and in the best of cases an extended recoveryperiod.

With the advent of percutaneous tranluminal coronary angioplasty (PTCA)in 1977, the scene changed dramatically. Using catheter techniquesoriginally developed for heart exploration, inflatable balloons wereemployed to re-open occluded regions in arteries. The procedure wasrelatively non-invasive, took a very short time compared to by-passsurgery and the recovery time was minimal. However, PTCA brought with itother problems such as vasospasm and elastic recoil of the stretchedarterial wall which could undo much of what was accomplished and, inaddition, it created a new disease, restenosis, the re-clogging of thetreated artery due to neointimal hyperplasia.

The next improvement, advanced in the mid-1980s was the use of a stentto maintain the luminal diameter after PTCA. This for all intents andpurposes put an end to vasospasm and elastic recoil but did not entirelyresolve the issue of restenosis. That is, prior to the introduction ofstents, restenosis occurred in from 30-50% of patients undergoing PTCA.Stenting reduced this to about 15-20%, much improved but still more thandesirable.

In 2003, drug-eluting stents or DESs were introduced. The drugsinitially employed with the DES were cytostatic compounds, that is,compounds that curtailed the proliferation of cells that resulted inrestenosis. The occurrence of restenosis was thereby reduced to about5-7%, a relatively acceptable figure. However, the use of DESsengendered a new problem, late stent thrombosis, the forming of bloodclots long after the stent was in place. It was hypothesized that theformation of blood clots was most likely due to delayed healing, aside-effect of the use of cytostatic drugs.

What is needed is an implantable medical device that includes apro-healing influence to counter the delayed healing due to the elutingdrugs. While this would be particularly useful with regard to coronarystents, it would also provide substantial benefit to any manner ofimplantable medical device. For instance, it has been stated that theoccurrence of restenosis in the case of lower extremity percutaneousangioplasty is particularly unacceptable (Paul S. Teirstein,Circulation, 2000, 102:2674) and it would be expected that thissituation would also be amenable to the effects of stents havingpro-healing properties. The present invention provides such implantablemedical devices.

SUMMARY

Thus, in one aspect, the current invention relates to an implantablemedical device, comprising:

-   a device body;-   an optional primer layer disposed over the device body;-   a drug reservoir layer disposed over the device body or the primer    layer if opted, wherein the drug reservoir layer comprises one or    more therapeutic agents;-   an optional rate-controlling layer disposed over at least a portion    of the drug reservoir layer, if opted; and,-   an optional top-coat layer disposed as an outermost layer over the    device body, the primer layer, if opted, the drug reservoir layer,    if opted, or the rate-limiting layer, if opted, wherein:-   at least one of the layers comprises a poly(ester-amide) having the    formula:

[X_(m)/Y_(p)/Z_(n)]_(r)(M_(w), s, t, v)

wherein:

-   m is an integer from 0 to about 200;-   p is an integer from 0 to about 200;-   n is an integer from 0 to about 200;-   r is an integer from 1 to about 3000;-   Mn is from about 10,000 Da to about 1,000,000 Da;-   s is a number from 0 to 1, inclusive;-   t is a number from 0 to 1, inclusive;-   v is a number from 0 to 1, inclusive; wherein s+t+v 1;-   X has the chemical structure:

-   Y has the chemical structure:

-   Z has the chemical structure:

wherein:

R₁, R_(1′) and R₄ are independently selected from the group consistingof (1C-12C)alkyl and (2C-12C)alkenyl;

R₂, R_(2′), R_(2″) and R_(2′″) are independently selected from the groupconsisting of hydrogen and (1C-4C)alkyl, wherein:

-   -   the alkyl group is optionally substituted with a moiety selected        from the group consisting of —OH, —O(1C-4C)alkyl, —SH,        —S(1C-4C)alkyl, —SeH, —COR₆, —NHC(NH)NH₂, imidazol-2-yl,        imidazole-5-yl, indol-3-yl, phenyl, 4-hydroxyphenyl and        4-[(1C-4C)alkylO]phenyl, wherein:        -   R₆ is selected from the group consisting of —OH,            —O(1C-4C)alkyl, —NH₂, —NH(1C-4C)alkyl,            —N(1C-4C)alkyl₁(1C-4C)alkyl₂, a stable nitroxide,            —O(CH)₂OP(═O)(O⁻)OCH₂CH₂N⁺(CH₃)₃, —O(CH₂CH₂O)_(q)CH₂CH₂OR₇            and

where:

-   -   -   -   R₇ is selected from the group consisting of hydrogen,                (1C-4C)alkyl, —C(O)CH═CH₂ and —C(O)C(CH₃)═CH₂;                or

    -   one or more of R₂, R_(2′), R_(2″) and R_(2′″) may form a bridge        between the carbon to which it is attached and the adjacent        nitrogen, the bridge comprising —CH₂CH₂CH₂—;

    -   R₃ is selected from the group consisting of (1C-12C)alkyl and        (2C-12C)alkenyl, (3C-8C)cycloalkyl and —(CH₂CH₂O)_(q)CH₂CH₂—;

    -   R₅ is selected from the group consisting of —CH(COR₆)CH₂S—,        —CH(COR₆)CH₂O—, —CH(COR₆)(CH₂)₄NH—, —(CH₂)₄CH(COR₆)NH—,        —CH(COR₆)CH(CH₃)O—,

and

and,

-   -   q is an integer from 1 to 600, inclusive.

In an aspect of this invention, M_(n) is from about 20,000 Da to about500,000 Da.

In an aspect of this invention, at least an outermost layer comprisesthe poly(ester-amide).

In an aspect of this invention, the outermost layer is a topcoat layer.

In an aspect of this invention R₁ is selected from the group consistingof —(CH₂)₄—, —(CH₂)₈—, and —CH₂CH═CHCH₂— and R_(1′) and R₄ are selectedfrom the group consisting of —(CH₂)₄— and —(CH₂)₈—.

In an aspect of this invention, R₂ is —CH₂CH(CH₃)₂.

In an aspect of this invention, R₃ is —(CH₂)₆— and R_(3′) is

In an aspect of this invention R₅ is —(CH₂)₄COR₆NH—, wherein R₆ isselected from the group consisting of —O(CH)₂OP(═O)(O⁻)OCH₂CH₂N⁺(CH₃)₃and —O(CH₂CH₂O)_(q)CH₂CH₂OR₇, wherein R₇ is selected from the groupconsisting of hydrogen, (1C-4C)alkyl, —C(O)CH═CH₂ and —C(O)C(CH₃)═CH₂.

In an aspect of this invention, p=0.

In an aspect of this invention, when p=0, R₁ and R₄ are independentlyselected from the group consisting of —(CH₂)₄— and —(CH₂)₈—.

In an aspect of this invention, when p=0, R₂ and R_(2′) areindependently selected from the group consisting of —CH₃,—CH₂CH₂NHC(NH)NH₂, —CH₂CONH₂, —CH₂COOH, —CH₂SH, —CH₂CH₂COOH,—CH₂CH₂CONH₂, —CH₂NH₂,

—CH(CH₃)CH₂CH₃. —CH₂CH(CH₃)₂, —(CH₂)₄NH₂, (CH₂)₂SCH₃,

CH₂OH, —CH(CH₃)OH,

—CH(CH₃)₂ and —CH₂CH₂CH₂—, wherein the second carbon is covalentlybonded to the nitrogen adjacent to the carbon to which R₂ is bonded.

In an aspect of this invention, when p=0, R₃ is selected from the groupconsisting of —(CH₂)₃—, —(CH₂)₆— and —(CH₂CH₂O)_(q)CH₂CH₂—, wherein q isan integer from 1 to 10, inclusive.

In an aspect of this invention, when p=0, R₅ is —(CH₂)₄CH(COR₆)NH—,wherein R₆ is selected from the group consisting of a stable nitroxide,

—O(CH)₂OP(═O)(O⁻)OCH₂CH₂N⁺(CH₃)₃ and —O(CH₂CH₂O)_(q)CH₂CH₂OR₇, whereinR₇ is selected from the group consisting of hydrogen, (1C-4C)alkyl,—C(O)CH═CH₂ and —C(O)C(CH₃)═CH₂.

In an aspect of this invention, when p=0, R₂ and R_(2′) are identical.

In an aspect of this invention, when p=0, R₂ and R_(2′) are—CH₂CH(CH₃)₂.

In an aspect of this invention, when p=0, the stable nitroxide isselected from the group consisting of

In an aspect of this invention, when p=0, the stable nitroxide is

In an aspect of this invention, when p=0, R₆ is

In an aspect of this invention, p=0 and n=0.

In an aspect of this invention, when p=0 and n=0, R₂ and R_(2′) areselected from the group consisting of —CH₃, —H₂CH₂NHC(NH)NH₂, —CH₂CONH₂,—CH₂COOH, —CH₂SH, —CH₂CH₂COOH, —CH₂CH₂CONH₂, —CH₂NH₂

—CH(CH₃)CH₂CH₃. —CH₂CH(CH₃)₂, —(CH₂)₄NH₂, (CH₂)₂SCH₃,

CH₂OH, —CH(CH₃)OH,

CH(CH₃)₂ and —CH₂CH₂CH₂—, wherein the second carbon is covalently bondedto the nitrogen adjacent to the carbon to which R₂ is bonded.

In an aspect of this invention, when p=0 and n=0, R₁ is selected fromthe group consisting of —(CH₂)₄—, —(CH₂)₈— and —CH₂CH═CHCH₂—.

In an aspect of this invention, when p=0 and n=0, R₂ and R_(2′) are thesame.

In an aspect of this invention, when p=0 and n=0, R₂ and R_(2′) areCH₂CH(CH₃)₂.

In an aspect of this invention, when p=0 and n=0, R₃ is selected fromthe group consisting of (3C-8C) alkyl, —(CH₂CH₂O)_(q)CH₂CH₂—, wherein qis an integer from 1 to 10, inclusive,

and

In an aspect of this invention, when p=0 and n=0, q is 2.

In an aspect of this invention, when p=0 and n=0, R₃ is selected fromthe group consisting of —(CH₂)₃— and —(CH₂)₆—.

In an aspect of this invention, when p=0 and n=0, R₃ is

In an aspect of this invention, when p=0 and n=0, R₂ and R_(2′) arebenzyl.

In an aspect of this invention, the implantable medical device furthercomprises a drug reservoir layer and a rate-controlling layer, whereinthe rate-controlling layer comprises a polymer selected from the groupconsisting of poly(I-lactide), poly(D-lactide), poly(D,L-lactide),poly(meso-lactide), poly(L-lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(meso-lactide-co-glycolide) and an combination thereof.

In an aspect of this invention, the rate-controlling layer comprisespoly(D,L-lactide).

In an aspect of this invention, the implantable medical device furthercomprises a drug reservoir layer, wherein the drug reservoir layercomprises one or more drugs disposed neat over the primer layer.

In an aspect of this invention, the implantable medical device furthercomprises a drug reservoir layer, wherein the drug reservoir layercomprises one or more polymers.

In an aspect of this invention, the therapeutic agent is everolimus.

In an aspect of this invention, the drug reservoir layer polymer isselected from the group consisting of poly(vinylidene fluoride) andpoly(vinylidene fluoride-co-hexafluoropropylene).

In an aspect of this invention, the implantable medical device furthercomprises a primer layer, wherein the primer layer comprisespoly(n-butyl methacrylate).

An aspect of this invention is a stent, comprising a poly(n-butylmethacrylate) primer, a poly(vinylidene fluoride-co-hexafluoropropylene)drug reservoir layer comprising everolimus and a topcoat layercomprising a poly(ester-amide).

In an aspect of this invention, the poly(ester-amide) in the aspectimmediately above is selected from the group consisting of PEA-TEMPO andPEA-BZ.

In an aspect of this invention, one or more of R₂, R_(2′), R_(2″),R_(2′″) and R₅ comprises a pendant —COR₆ group wherein each R₆ isindependently selected from the group consisting of a stable nitroxideentity, benzylO—, —O(CH₂)₂OP(═O)(O)CH₂CH₂N⁺(CH₃)₃ and—O(CH₂CH₂O)_(q)CH₂CH₂OR₇.

In an aspect of this invention, an outermost layer comprises thepoly(ester-amide).

In an aspect of this invention, the outermost layer is a topcoat layer.

In an aspect of this invention, in the aspect immediately above, thestable nitroxide is selected from the group consisting of

In an aspect of this invention, in the aspect two paragraphs above, q is1-10, inclusive.

In an aspect of this invention, in the aspect three paragraphs above, qis 300-600, inclusive.

In an aspect of this invention, in the aspect four paragraphs above, R₆is —O(CH₂)₂OP(═O)(O)CH₂CH₂N⁺(CH₃)₃.

In an aspect of this invention, the implantable medical device is astent.

DETAILED DESCRIPTION BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 graphically depicts the inflammatory and cellular responseelicited by Impra® graft material, Hemashield® graft material, PEA-TEMPOand PEA-BZ at 14 days post-implantation in rat epicardial tissue.

FIG. 2 graphically depicts the inflammatory and cellular responseelicited by Impra® graft material, Hemashield® graft material, PEA-TEMPOand PEA-BZ at 30 days post-implantation in rat epicardial tissue.

FIG. 3 graphically depicts endothelial cell coverage of a PEA-coatedstent, a BMS and a Solef® (poly(vinylidenefluoride-co-hexafluoropropylene)-coated stent.

FIG. 4 graphically depicts the percentage everolimus released by a stentwithout a topcoat, which establishes a target release rate, comparedwith a stent having a topcoat of a poly(ester-amide) of this invention.

DISCUSSION

Use of the singular herein includes the plural and visa versa unlessexpressly stated to be otherwise. That is, “a” and “the” refer to one ormore of whatever the word modifies. For example, “a therapeutic agent”includes one such agent, two such agents, etc. Likewise, “the layer” mayrefer to one, two or more layers and “the polymer” may mean one polymeror a plurality of polymers. By the same token, words such as, withoutlimitation, “layers” and “polymers” would refer to one layer or polymeras well as to a plurality of layers or polymers unless, again, it isexpressly stated or obvious from the context that such is not intended.

As used herein, any words of approximation such as without limitation,“about,” “essentially,” “substantially” and the like mean that theelement so modified need not be exactly what is described but can varyfrom the description by as much as ±15% without exceeding the scope ofthis invention.

As used herein, “if opted” means that the item being discussed isoptional and if the option is exercised the condition that follows thephrase will pertain.

As used herein, an “implantable medical device” refers to any type ofappliance that is totally or partly introduced, surgically or medically,into a patient's body or by medical intervention into a natural orifice,and which is intended to remain there after the procedure. The durationof implantation may be essentially permanent, i.e., intended to remainin place for the remaining lifespan of the patient; until the devicebiodegrades; or until it is physically removed. Examples of implantablemedical devices include, without limitation, implantable cardiacpacemakers and defibrillators; leads and electrodes for the preceding;implantable organ stimulators such as nerve, bladder, sphincter anddiaphragm stimulators, cochlear implants; prostheses, vascular grafts,self-expandable stents, balloon-expandable stents, stent-grafts, grafts,PFO closure devices, arterial closure devices, artificial heart valvesand cerebrospinal fluid shunts.

An implantable medical device specifically designed and intended solelyfor the localized delivery of a therapeutic agent is within the scope ofthis invention.

As used herein, “device body” refers to a fully formed implantablemedical with an outer surface to which no coating or layer of materialdifferent from that of which the device itself is manufactured has beenapplied. By “outer surface” is meant any surface however spatiallyoriented that is in contact with bodily tissue or fluids. A commonexample of a “device body” is a BMS, i.e., a bare metal stent, which, asthe name implies, is a fully-formed usable stent that has not beencoated with a layer of any material different from the metal of which itis made on any surface that is in contact with bodily tissue or fluids.Of course, device body refers not only to BMSs but also to any uncoateddevice regardless of what it is made of.

Implantable medical devices made of virtually any material, i.e.,materials presently known to be useful for the manufacture ofimplantable medical devices and materials that may be found to be so inthe future, may be used with a coating of this invention. For example,without limitation, an implantable medical device useful with thisinvention may be made of one or more biocompatible metals or alloysthereof including, but not limited to, cobalt-chromium alloy (ELGILOY,L-605), cobalt-nickel alloy (MP-35N), 316L stainless steel, highnitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy(NITINOL), tantalum, platinum, platinum-iridium alloy, gold andcombinations thereof.

Implantable medical devices may also be made of polymers that arebiocompatible and biostable or biodegradable, the latter term includingbioabsorbable and bioerodable.

As used herein, “biocompatible” refers to a polymer that both in itsintact, as synthesized state and in its decomposed state, itsdegradation products, are not toxic, or at least are minimally toxic, toliving tissue; does not, or at least minimally and reparably, injure(s)living tissue; and/or does not, or at least minimally and controllably,cause(s) an immunological reaction in living tissue.

Among useful biocompatible, relatively biostable polymers are, withoutlimitation, polyacrylates, polymethacryates, polyureas, polyurethanes,polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers,polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins,polysiloxanes and epoxy resins.

Biocompatible, biodegradable polymers include naturally-occurringpolymers such as, without limitation, collagen, chitosan, alginate,fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronicacid, heparin, glycosaminoglycans, polysaccharides and elastin.

One or more synthetic or semi-synthetic biocompatible, biodegradablepolymers may also be used to fabricate an implantable medical deviceuseful with this invention. As used herein, a synthetic polymer refersto one that is created wholly in the laboratory while a semi-syntheticpolymer refers to a naturally-occurring polymer than has been chemicallymodified in the laboratory. Examples of synthetic polymers include,without limitation, polyphosphazines, polyphosphoesters,polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates,polyanhydrides, polyesters, polyorthoesters, polycarbonates,polyiminocarbonates, polyamino acids, polyoxymethylenes,poly(ester-amides) and polyimides.

Blends and copolymers of the above polymers may also be used and arewithin the scope of this invention. Based on the disclosures herein,those skilled in the art will recognize those implantable medicaldevices and those materials from which they may be fabricated that willbe useful with the coatings of this invention.

At present, preferred implantable medical devices for use with thecoatings of this invention are stents.

A stent refers generally to any device used to hold tissue in place in apatient's body. Particularly useful stents, however, are those used forthe maintenance of the patency of a vessel in a patient's body when thevessel is narrowed or closed due to diseases or disorders including,without limitation, tumors (in, for example, bile ducts, the esophagus,the trachea/bronchi, etc.), benign pancreatic disease, coronary arterydisease, carotid artery disease, renal artery disease and peripheralarterial disease such as atherosclerosis, restenosis and. vulnerableplaque. Vulnerable plaque (VP) refers to a fatty build-up in an arterythought to be caused by inflammation. The VP is covered by a thinfibrous cap that can rupture leading to blood clot formation. A stentcan be used to strengthen the wall of the vessel in the vicinity of theVP and act as a shield against such rupture. A stent can be used in,without limitation, neuro, carotid, coronary, pulmonary, aortic, renal,biliary, iliac, femoral and popliteal as well as other peripheralvasculatures. A stent can be used in the treatment or prevention ofdisorders such as, without limitation, thrombosis, restenosis,hemorrhage, vascular dissection or perforation, vascular aneurysm,chronic total occlusion, claudication, anastomotic proliferation, bileduct obstruction and ureter obstruction.

In addition to the above uses, stents may also be employed for thelocalized delivery of therapeutic agents to specific treatment sites ina patient's body. In fact, therapeutic agent delivery may be the solepurpose of the stent or the stent may be primarily intended for anotheruse such as those discussed above with drug delivery providing anancillary benefit.

A stent used for patency maintenance is usually delivered to the targetsite in a compressed state and then expanded to fit the vessel intowhich it has been inserted. Once at a target location, a stent may beself-expandable or balloon expandable. In any event, due to theexpansion of the stent, any coating thereon must be flexible and capableof elongation.

As used herein, “optional” means that the element modified by the termmay or may not be present. For example, without limitation, a devicebody (db) that has coated on it an “optional” primer layer(pl), an“optional” drug reservoir layer (dr), an “optional” rate-controllinglayer (rc) and a top-coat layer (tc) (which it should be noted is notoptional herein) refers, without limitation, to any of the followingdevices: db+tc, db+dr+tc, db+dr+rc+tc, db+pl+tc, db+pl+dr+tc anddb+pl+dr+rc+tc.

As used herein, a “primer layer” refers to a coating consisting of apolymer or blend of polymers that exhibit good adhesion characteristicswith regard to the material of which the device body is manufactured andgood adhesion characteristic with regard to whatever material is to becoated on the device body. Thus, a primer layer serves as anintermediary layer between a device body and materials to be affixed tothe device body and is, therefore, applied directly to the device body.Examples without limitation, of primers include silanes, titanates,zirconates, silicates, parylene, vinyl alcohol copolymers, acrylic acidcopolymers, methacrylic acid copolymers, polyethyleneamine,polyallylamine, acrylate and methacrylate polymers with poly(n-butylmethacrylate) being a presently preferred primer.

As use herein, a material that is described as a layer “disposed over”an indicated substrate, e.g., without limitation, a device body oranother layer, refers to a relatively thin coating of the materialapplied, preferably at present, directly to essentially the entireexposed surface of the indicated substrate. By “exposed surface” ismeant that surface of the substrate that, in use, would be in contactwith bodily tissues or fluids. “Disposed over” may, however, also referto the application of the thin layer of material to an intervening layerthat has been applied to the substrate, wherein the material is appliedin such a manner that, were the intervening layer not present, thematerial would cover substantially the entire exposed surface of thesubstrate.

As used herein, “drug reservoir layer” refers either to a layer of oneor more therapeutic agents applied neat or to a layer of polymer orblend of polymers that has dispersed within its three-dimensionalstructure one or more therapeutic agents. A polymeric drug reservoirlayer is designed such that, by one mechanism or another, e.g., withoutlimitation, by elution or as the result of biodegradation of thepolymer, the therapeutic substance is released from the layer into thesurrounding environment.

As used herein, “therapeutic agent” refers to any substance that, whenadministered in a therapeutically effective amount to a patientsuffering from a disease, has a therapeutic beneficial effect on thehealth and well-being of the patient. A therapeutic beneficial effect onthe health and well-being of a patient includes, but it not limited to:(1) curing the disease; (2) slowing the progress of the disease; (3)causing the disease to retrogress; or, (4) alleviating one or moresymptoms of the disease. As used herein, a therapeutic agent alsoincludes any substance that when administered to a patient, known orsuspected of being particularly susceptible to a disease, in aprophylactically effective amount, has a prophylactic beneficial effecton the health and well-being of the patient. A prophylactic beneficialeffect on the health and well-being of a patient includes, but is notlimited to: (1) preventing or delaying on-set of the disease in thefirst place; (2) maintaining a disease at a retrogressed level once suchlevel has been achieved. by a therapeutically effective amount of asubstance, which may be the same as or different from the substance usedin a prophylactically effective amount; or, (3) preventing or delayingrecurrence of the disease after a course of treatment with atherapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount, has concluded.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably.

As used herein, “rate-controlling layer” refers to a polymeric layerthat is applied over a drug reservoir layer to modify the rate ofrelease into the environment of the therapeutic agents from the drugreservoir layer. A rate-controlling layer may be used simply to “tune”the rate of release of a therapeutic agent to exactly that desired bythe practitioner or it may be a necessary adjunct to the constructbecause the polymer or blend of polymers with which the therapeuticagent is compatible with regard to coating as a drug reservoir layer maybe too permeable to the therapeutic substance resulting in too rapidrelease and delivery of the therapeutic substance into a patient's body.A non-limiting example is an everolimus drug reservoir layer comprisingPEA-TEMPO (a poly(ester-amide) to which2,2,6,6-tetramethyl-4-aminopiperidineoxyl has been covalently appended).While PEA-TEMPO has very desirable in vivo properties, it is quitepermeable to everolimus. Thus, sustained release (i.e., release of atherapeutically effective amount of a drug over an extended period oftime which may be a few days, a few months, or even longer) ofeverolimus from a poly(ester-amide) polymer matrix is difficult and insome cases impossible to achieve. To ameliorate this situation, arate-controlling polymer or blend of polymers through which theeverolimus must pass can be applied over the more PEA-TEMPO layer. Thereduced permeability of everolimus through the rate-controlling layermay be due, without limitation, to inherent characteristics of thepolymer and its interaction with a given therapeutic agent or it may bedue to such factors as cross-linking of the rate-controlling polymer.

A poly(ester-amide) refers to a polymer that has in its backbonestructure both ester and amide bonds. For example, the following formularepresents a poly(ester-amide) of this invention:

X, Y and Z refer to the constitutional units, i.e., the repeating units,of the polymer. For example, in the polymer

is the X constitutional unit and

is the Z constitutional unit, Y being absent, i.e., p is 0. Theconstitution units themselves can be the product of the reactions ofother compounds. For example, without limitation, the X constitutionalunit above may comprises the reaction of an amino acid,

with a diol, HO—(R₃)—OH, to give a diamino ester,

which is then reacted with a diacid,

to give the constitutional unit. The amine group, the carboxylic acidgroup or the hydroxyl group may be “activated,” i.e., rendered morechemically reactive, to facilitate the reactions if desired; suchactivating techniques are well-known in the art and the use of any suchtechniques is within the scope of this invention. A non-limiting exampleof the synthesis of an exemplary but not limiting X constitution unithaving the above general structure is the reaction of 1,6-hexane diolwith I-leucine to give the diamino diester, which is then reacted withsebacic acid to give X. Constitutional unit Y can be obtained by thesame reactions as those affording X but using one or more differentreactants such that the resulting constitutional units X and Y arechemically different or Y may result from the reaction of a diacid witha tri-functional amino acid wherein two of the functional groups arecapable of reacting with the diacid. As example of the foregoing wouldbe the reaction of sebacic acid or an activated derivative thereof, withI-lysine, i.e., 2,6-diaminohexanoic acid.

With regard to the synthesis of the poly(ester-amide)s of thisinvention, it will be noted that no specific reactions or reactionconditions are exemplified herein. This is because the reactions andreaction conditions both for the preparation of constitutional units andfor the preparation of the final poly(ester-amide) comprise standardorganic and polymer chemistry well-known to those of ordinary skill inthe art and, therefore, those skilled artisans will be able to prepareany of the compounds herein without undue experimentation based on thedisclosures herein.

As for the amino acids selected for the preparation ofpoly(ester-amide)s of this invention, any may be use; however, atpresent it is preferred that the amino acids be selected from the groupcommonly known as the standard amino acids or sometimes theproteinogenic amino acids because they are encoded by the normal geneticcode. There currently are 20 standard amino acids: alanine, arginine,asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine,histidine, isoleucine, leucine, lysine, methionine, phenyl alanine,proline, serine, threonine, tryptophan, tyrosine and valine. Relativelyrecently selenoadenine has been found to be incorporated into a numberof proteins and is included with the above as a useful amino acid forthe purposes of this invention. In naturally-occurring biologicalproteins, these amino acids exist primarily as I-enantiomers but for thepurposes of this invention they may be used as their I- or d-enantiomersor as racemic mixtures.

In the above formula, m, p and n are integers that represent the averagenumber of constitutional units X, Y and Z in an uninterrupted string or,if there is more than on, block; i.e., the number of X units before a Yunit is encountered, etc. The integers m, p and n can be any number,including 0; when two of m, p and n are 0, the resultingpoly(ester-amide) is a homopolymer.

In the above formula, r represents the total number of X, Y and Z unitsin the polymer and can be any integer from 1 to about 2500, with theproviso that the combination of m, p, n and r should provide apoly(ester-amide) that has a molecular weight within the range discussedbelow.

In the above formula, M_(n) represents the number average molecularweight of a poly(ester-amide) of this invention. Again, while anymolecular weight that results in a polymer that has the requisiteproperties to useful with the implantable medical devices of thisinvention, properties that are well-known to those skilled in the art,is within the scope of this invention, at present the number averagemolecular weight of a poly(ester-amide) of this invention is from about10,000 Da (Daltons) to about 1,000,000 Da, preferably at present fromabout 20,000 Da to about 500,000 Da.

Also in the above formula, s, t and v represent the mole fraction ofeach of the constitutional units. Each of s, t and v is a number between0 and 1, inclusive with s+t+v=1. It is understood that the mole fractionand the number of constitutional units are related and the designationof one will affect the other.

As noted s, t and v may each be 0, 1 or any fraction between. There are,however, certain provisos: (1) if an additional prohealing entity ispresent on one of the constitutional units, that constitutional unitmust be at least 0.02 mol fraction of the polymer; and (2) m and p canboth be 0 only if R₅ is selected from the group consisting of—CH(COR₆)CH₂S—, —CH(C(O)R₆CH₂O—, —CH(COR₆)CH(CH₃)O— and

because otherwise the resulting homopolymer would not be apoly(ester-amide). Other than the preceding provisos, any values of s, tand v that provides a polymer having desirable properties for theintended use, e.g., as a drug reservoir layer, a rate-controlling layer,etc., and those skilled in the art will be readily able to make suchvariations and determine if the resulting polymer as the requisiteproperties based on the disclosures herein without undueexperimentation.

The polymers of this invention may be regular alternating polymers,random alternating polymers, regular block polymers, random blockpolymers or purely random polymers unless expressly noted otherwise. Aregular alternating polymer has the general structure: . . .x-y-z-x-y-z-x-y-z- . . . A random alternating polymer has the generalstructure: . . . x-y-x-z-x-y-z-y-z-x-y- . . . , it being understood thatthe exact juxtaposition of the various constitution units may vary. Aregular block polymer has the general structure: . . .x-x-x-y-y-y-z-z-z-x-x-x . . . , while a random block polymer has thegeneral structure: . . . x-x-x-z-z-x-x-y-y-y-y-z-z-z-x-x-z-z-z- . . .Similarly to the situation above regarding regular and alternatingpolymers, the juxtaposition of blocks, the number of constitutionalunits in each block and the number of blocks in block polymers of thisinvention are not in any manner limited by the preceding illustrativegeneric structures.

Constitutional unit Z, on the other hand, is the result of the reactionof a diacid with a tri-functional amino acid wherein two of thefunctional groups are capable of reacting with the diacid. As examplewould be the reaction of sebacic acid or an activated derivativethereof, with I-lysine, 2, 6-diaminohexanoic acid, the two amino groupsbeing capable of reacting with the diacid carboxyl groups to formamides.

The poly(ester-amides) of this invention may be used as is, that is, asthe product of amino acids, diacids and diols as described above becauseit has been found that the poly(ester-amide)s of this invention exhibitpro-healing properties in their own right. It is an aspect of thisinvention, however, that a poly(ester-amide) of this invention may befurther modified by the attachment of an additional pro-healing moietyto an appropriate pendant group attached to the polymer backbone. Bypro-healing moiety is meant a substituent group that is biocompatibleand that aids in the amelioration of inflammation and/or in theendothelialization of the implantable medical device. Such substituentgroups include, without limitation, stable nitroxides;phosphorylcholine, —O(CH)₂OP(═O)(O—)OCH₂CH₂N⁺(CH₃)₃, nitric oxidedonors, nitric oxide generating catalysts that utilize nitrosothiols,oligomers of ethylene glycol or ethylene oxide; poly(ethylene glycol)and end-group modified derivatives thereof, i.e.,—O(CH₂CH₂O)_(q)CH₂CH₂OR₇, wherein R₇ is selected from the groupconsisting of hydrogen, (1C-4C)alkyl, —C(O)CH═CH₂, —C(O)C(CH₃)═CH₂ andphosphorylcholine. If R₇ comprises a double bond, double bonds ondifferent polymer chains may be reacted with one another using UV lightor a free radical initiator to give a crosslinked poly(ester-amide).

As used herein, “alkyl” refers to a straight or branched chain fullysaturated (no double or triple bonds) hydrocarbon (carbon and hydrogenonly) group. The alkyl groups of this invention may range from C₁ toC₁₂, preferably C₂ to C₁₀ and currently most preferably C₃ to C₈.Examples of alkyl groups include, but are not limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl,ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. In addition, as used herein “alkyl” includes “alkylene”groups, which refer to straight or branched fully saturated hydrocarbongroups having two rather than one open valences for bonding to othergroups. Examples of alkylene groups include, but are not limited tomethylene, —CH₂—, ethylene, —CH₂CH₂—, propylene, —CH₂CH₂CH₂—,n-butylene, —CH₂CH₂CH₂CH₂—, sec-butylene, —CH₂CH₂CH(CH₃)— and the like.

As used herein, “mC to nC,” wherein m and n are integers refers to thenumber of possible carbon atoms in the indicated group. That is, thegroup can contain from “m” to “n”, inclusive, carbon atoms. An alkylgroup of this invention may comprise from 1 to 12 carbon atoms, that is,m may bel and n may be 12. Of course, a particular alkyl group may bemore limited, for instance without limitation, to 3 to 8 carbon atoms,in which case it would be designate as a (3C-8C)alkyl group. The numbersare inclusive and incorporate all straight or branched chain structureshaving the indicated number of carbon atoms. For example withoutlimitation, a “C₁ to C₄ alkyl” group refers to all alkyl groups havingfrom 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, CH₃CH(CH₃)—,CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃CH—.

As use herein, “cycloalkyl” refers to an alkyl group in which the endcarbon atoms of the alkyl chain are covalently bonded to one another. Incycloalkyl groups, the numbers “m” to “n” refer to the number of carbonatoms in the ring so formed. Thus for instance, a (3C-8C)cycloalkylgroup refers to a three, four, five, six, seven or eight member ring,that is, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

As used herein, “bicycloalkyl” refers to two cycloalkylgroups bondedtogether by a single covalent bond. An example, without limitation, of abicycloalkyl group is bicyclohexane,

As used herein, “benzyl” refers to a phenylmethylene,

group.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds.

If a group of this invention is described as being “optionallysubstituted” it means that that group may be unsubstituted orsubstituted with one or more of the indicated substituents.

Standard shorthand designations well-known to those skilled in the artare used throughout this application. Thus the intended structure willeasily be recognizable to those skilled in the art based on the requiredvalency of any particular atom with the understanding that all necessaryhydrogen atoms are provided. For example, —COR, because carbon istetravalent, must refer to the structure

as that is the only way the carbon can be tetravalent without theaddition of unshown hydrogen or other atoms. Similarly,—O(CH)₂OP(═O)(O—)OCH₂CH₂N⁺(CH₃)₃ refers to the structure

Likewise, it is understood by those skilled in the chemical arts thatso-called stick structure, exemplified by

represents the structure

that is, each terminus is capped with a CH₃ group and the apex of eachangle is a carbon atom with the requisite number of hydrogens attached.

The designation of two or more alkyl moieties as alkyl₁, alkyl₂, etc.,means that the alkyl groups may be the same or different.

As used herein, a “stable nitroxide” refers to an isolatableparamagnetic organic compound having the generic structure RR′N—Owherein R and R′ may be aliphatic or may join to form a ring which maybe acyclic or aromatic. In addition, for the purposes of this invention,the stable nitroxide must also contain at least one functional groupthrough which the nitroxide may be covalently bonded to apoly(ester-amide) of this invention. For example, without limitation,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl can be reacted with apendant carboxylic acid group of, without limitation, lysine thatcomprises the backbone of a poly(ester-amide) of this invention, to forman amide. Other such functional groups that will afford covalentlybonded stable nitroxides will be evident to those skilled in the artbased on the disclosures herein and are within the scope of thisinvention.

As used herein, to dispose a layer of “neat” therapeutic agent simplymeans that the therapeutic agent, once it is has been applied to asurface and any solvent used during the application has been allowed toevaporate, the therapeutic agent is the only constituent of the layer,i.e., there is essentially no solvent, no polymers, no excipients or anyother material in the layer other than the therapeutic agent inessentially the same purity as it had before being applied to thedevice.

The poly(ester-amides) of this invention have been found to havebeneficial pro-healing properties in vivo, in particular with regard toinflammation and neovascularization. For example, without limitation, acomparison of the inflammatory responses elicited in vivo by test discsmade of two poly(ester-amides) of this invention,co-poly-{[N,N′-sebacoyl-bis—(L-leucine)-1,6-hexylenediester]-[N,N′-sebacoyl-L-lysinebenzyl ester]} (PEA-BZ) andco-poly-{[N,N′-sebacoyl-bis—(L-leucine)-1,6-hexylenediester]-[N,N′-sebacoyl-L-lysine4-amino-2,2,6,6,-tetramethylpiperidine-1-oxyl amide]} (PEA-TEMPO), withthat caused by test discs made of two commercial graft polymers, Impra®ePTFE (expanded polytetrafluoroethylene), which has been shown to have alow inflammatory effect in vivo, and Hemaschield®, a polyester-basedgraft material which is known to be highly inflammatory (D. L. Salzmann,et al., Cardiovascular Pathology, 1999, 8(2):63-71) was carried out. Theresult of the comparison, which is discussed in greater detail inExample 1, was that both the PEA-TEMPO and PEA-BZ discs elicitedinflammatory responses that were equal to or less than that exhibited bythe Impra® disc.

In addition, a comparison of the neovascularization kinetics of a stentcoated with PEA-TEMPO was compared to that of a bare metal stent (BMS)and a poly(vinylidene fluoride-co-hexafluoropropylene) (SOLEF®) coatedstent (Example 2) when the stents were implanted in a bioengineeredvessel. The PEA-TEMPO-coated stent exhibited endothelial coverage only alittle lower than that exhibited by the BMS and substantially greaterthan that exhibited by the SOLEF® stent.

Based on the above results, together with the fact that thepoly(ester-amide) polymers of this invention are quite biocompatible, itis expected that coating implantable medical devices with a topcoat of apoly(ester-amide) herein should have a substantial beneficial effect onhealing in the vicinity of the implanted device and thereby reduce theoccurrence of problems associated with slow healing such as late-stagethrombosis. This should be particularly valuable with regard to drugeluting stents (DESs), which were initially introduced to counter thehigh rate of restenosis among recipients of BMSs. That is, whileovercoming some of the shortfalls of percutaneous coronary angioplasty(PTCA), such as elastic recoil of the arterial wall resulting in dynamicre-narrowing of the vessel, BMSs were found to still be susceptible torestenosis, albeit at a substantially lower rate than unstented PTCAs(15-20% in stented patients versus 30-50% in previous unstented PTCAs).In 2002 the first DESs designed to address BMS restenosis wereintroduced. The stents were engineered to slowly release a cytostaticdrug in the vicinity of the stent thereby slowing or preventing cellgrowth and resultant restenosis. DESs have reduced the incidence ofrestenosis to 5-7%. Since that time other drugs have been proposed foruse with DESs, both to further improve the clinical results of stentingand to effect localized delivery of drugs to target sites in a patient'sbody to overcome problems with the drugs such as toxicity,bioavailability, solubility, etc. Thus, therapeutic agents withanti-proliferative, anti-inflammatory, antineoplastic, antiplatelet,anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic,antiallergic and antioxidant properties have been proposed for use withDESs. Examples of suitable therapeutic agents include syntheticinorganic and organic compounds, proteins and peptides, polysaccharidesand other sugars, lipids, DNA and RNA nucleic acid sequences, antisenseoligonucleotides, antibodies, receptor ligands, enzymes, adhesionpeptides, blood clot agents such as streptokinase and tissue plasminogenactivator, antigens, hormones, growth factors, ribozymes, retroviralvectors, anti-proliferative agents such as rapamycin (sirolimus),40-O-2-hydroxyethyl)rapamycin (everolimus),40-O-3-hydroxypropyl)rapamycin, 40-O-2-hydroxyethyoxy)ethylrapamycin,40-O-tetrazolylrapamycin, 40-epi(N1-tetrazolyl)rapamycin (zotarolimus,ABT-578), paclitaxel, docetaxel, methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride,mitomycin, antiplatelet compounds, anticoagulants, antifibrin,antithrombins such as sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin,prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, thrombininhibitors such as Angiomax ä, calcium channel blockers such asnifedipine, coichicine, fibroblast growth factor (FGF) antagonists, fishoil (omega 3-fatty acid), histamine antagonists, lovastatin, monoclonalantibodies, nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine, nitric oxide or nitric oxide donors,super oxide dismutases, super oxide dismutase mimetic, estradiol,anticancer agents, dietary supplements such as vitamins,anti-inflammatory agents such as aspirin, tacrolimus, dexamethasone andclobetasol, cytostatic substances such as angiopeptin, angiotensinconverting enzyme inhibitors such as captopril, cilazapril orlisinopril, antiallergic agents is permirolast potassium,alpha-interferon, bioactive RGD, and genetically engineered epithelialcells. Other therapeutic agents which are currently available or thatmay be developed in the future for use with DESs may likewise be usedand all are within the scope of this invention.

With regard to the present invention, everolimus, an immunosuppressivemacrolide antibiotic, is a presently preferred therapeutic agent for usewith an implantable medical device of this invention.

While a poly(ester-amide) of this invention may be incorporated into anyof, any combination of, or all of the layers disposed over animplantable medical device of this invention, it is presently preferredthat the poly(ester-amide) be included in at least the outermost layercoated on the device.

As used herein, “outermost layer” simply refers to that layer ofmaterial disposed over an implantable medical device of this inventionthat is in contact with bodily fluids and/or tissues of the patient inwhom the device is implanted. The outermost layer is preferably atpresent a separate topcoat layer as described elsewhere herein but itmay be a rate-controlling layer, if a topcoat layer is not opted, oreven a drug reservoir layer if neither the topcoat layer nor therate-controlling layer is opted.

Thus, it is an aspect of this invention that a poly(ester-amide) topcoatcan be applied directly to the surface of a BMS. The healingcharacteristics of the poly(ester-amide) coating alone is expected tohave a salutary effect on restenosis even without added therapeuticagent.

It is also an aspect of this invention, however, to include thepoly(ester-amide) in a drug reservoir layer with no further layers beingapplied. This may be the case if the release profile of the therapeuticagent is not deleteriously affected by the inclusion of thepoly(ester-amide) in that layer. Techniques for determining if therelease profile of a particular therapeutic agent is acceptable for aparticular application is well within the knowledge of those skilled inthe art and need not be further described herein.

It is presently preferred, however, that an implantable medical deviceof this Invention comprises at least a topcoat layer and that thetopcoat layer comprise a poly(ester-amide) of this invention.

As noted, there may be layers disposed between the poly(ester-amide)topcoat and the device body. A common additional layer would be a primeras described above. A primer may be used if it is found that thematerial of which the device body is constructed does not adhere well tothe selected poly(ester-amide). While many primer polymers and polymerblends are known in the art and any of them can be used with the devicesand methods herein, a currently preferred class of primers is theacrylate polymers, copolymers and blends thereof. Preferable at present,poly(n-butyl methacrylate) is a preferred primer for use with thedevices and methods of this invention.

In lieu of or in addition to a primer, a drug reservoir layer may alsobe included between the device body and the topcoat layer. A separatedrug reservoir layer may be required if, without limitation, if is foundthat a desired therapeutic agent is not sufficiently compatible with thepoly(ester-amide) to provide the desired agent concentration, if thedesired release profile cannot be achieved, etc. The drug reservoirlayer may comprise simply the drug alone, that is, neat. This can beaccomplished by dissolving the drug in a suitable solvent, applying thesolution atop a primer that has been coated on the device body, andremoving the solvent leaving a layer of drug alone. Thepoly(ester-amide) topcoat may then be applied directly over the neatdrug layer.

In the alternative, the therapeutic agent may be formulated with apolymer or polymer blend. Thus, therapeutic agent and polymer can bedissolved in a suitable solvent or the polymer can be dissolved and thetherapeutic agent evenly dispersed in the polymer solution. The solutionor mixture can then be applied to either the device body or over aprimer layer. When the solvent is removed the drug is left suspended inpolymer. The polymer or polymer blend is selected to provide the desiredrelease profile. At times, however, a polymer that is compatible withthe drug may not afford the desired release profile or a polymer thatcan provide the desired profile is not sufficiently compatible with thedrug. This situation may be ameliorated by the inclusion of arate-controlling layer over the drug reservoir layer.

A rate-controlling layer, as the name implied, consists of a polymerthrough which the drug has been shown to elute at the desired rate whenthe correct polymer, correct polymer concentration and correct layerthickness is used. Again, these parameters are readily determinable bythose skilled in the art.

While, as noted above, an implantable medical device of this inventionmay encompass a large array of devices, a presently preferred device isa coronary stent and a presently preferred therapeutic agent for usewith the stent is everolimus. It is further presently preferred that animplantable medical device herein comprise a primer applied directly tothe device body and then a drug reservoir layer comprisingpoly(ethylidene fluoride) and everolimus, applied over the primer layer.A pro-healing poly(ester-amide) topcoat is then applied over the drugreservoir layer. A rate-controlling layer may be present but is notnecessarily so in that it has been determined (data not shown) thatcertain formulations of poly(vinylidenefluoride-co-hexafluoropropylene)/everolimus drug reservoir layersexhibit desirable release profiles. A more detailed description of thisaspect of this invention is provided in Example 3.

On the other hand, if release profiles not achievable usingpoly(ethylidene fluoride) or poly(ester-amide) in the drug reservoirlayer or poly(ester-amide) as a combination rate-controlling/topcoat aredesired, a separate rate-controlling layer may be used. Once again,different rate-controlling polymers or polymer blends useful withdifferent therapeutic agents are known in the art and all are within thescope of this invention so long as a poly(ester-amide) topcoat layer isapplied as the outermost layer on the implantable device.

As noted above, everolimus is a presently preferred therapeutic agentfor use herein. As it turns out, the presently preferred pro-healingpoly(ester-amide)s, PEA-TEMPO and PEA-BZ, are quite permeable toeverolimus and cannot alone provide achieve desirable sustained-releaseprofiles. If the drug reservoir layer likewise cannot provide completelythe desired profile, a rate-controlling layer may be disposed atop thedrug reservoir layer can be employed. Presently preferred polymersuseful for establishing desired everolimus release profiles arepoly(L-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide),poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide) or anycombination thereof. Most preferred at present in poly(D,L-lactide). Aconcrete, but in no way limiting, example of an implantable medicaldevice that follows the above protocol would be:

-   a 12 mm Vision® stent;-   168 μg total weight of a 1:2 wt/wt mixture of everolimus/PEA-TEMPO    drug reservoir layer disposed over the stent;-   40 μg of poly(D,L-lactide) disposed as a rate-controlling layer over    the drug reservoir layer; and,-   a 75 μg of PEA-TEMPO as a pro-healing topcoat layer.

Another, likewise non-limiting, example would be:

-   100 μg of PEA-TEMPO applied to a 12 mm Vision® stent as a primer    layer;-   56 μg neat everolimus applied atop the primer layer as the drug    reservoir layer;-   40 μg of poly(D,L-lactide) applied atop the neat everolimus layer as    a rate-controlling layer; and,-   75 μg of PEA-TEMPO as a topcoat pro-healing layer.

As noted previously, a separate rate-controlling layer may not benecessary if the therapeutic agent is sufficiently compatible with aneffective rate-controlling polymer to be included in the same layer withit. Such is the case with everolimus and poly(D,L-lactide), Thus yetanother non-limiting construct of this invention is envisioned tocomprise:

-   100 μg poly(D,L-lactide) coated on a 12 mm Vision® stent;-   112 μg total weight of a 1:1 everolimus/poly(D,L-lactide) drug    reservoir layer/rate-controlling layer; and,-   150 μg of PEA-TEMPO as a pro-healing topcoat;

EXAMPLES Example 1

The inflammatory response of PEA-TEMPO and PEA-BZ was evaluated using arat epicardial model. Hemashield® graft material was used as a highlyinflammatory control and Impra® ePTFE graft material was used as aminimally inflammatory control. Four millimeter diameter 300 μm thickdiscs of each polymer were implanted onto rat epicardial surface and theinflammation level was measured at 14 days and at 30 days. The controldiscs exhibited inflammatory and cellular responses typical of thosematerials. Both PEA-TEMPO and PEA-BZ exhibited cellular and inflammatoryresponses that were equal to or less than that of the Impra® disc. Theresults are shown graphically in FIGS. 1 and 2.

Example 2

The re-endothelialization kinetics of PEA-TEMPO coated on a stent werecompared to those of a bare metal stent (BMS) and a stent coated withSolef® (poly(vinylidene fluoride-co-hexafluoropropylene). Medium Vision®4.0 X 18 mm stents were used bare, coated with 1494 μg of PEA-TEMPO orcoated with 767 μg of Solef®. The stents were implanted in abioengineered vessel and evaluated after 7 days. The stented vesselswere stained with bisbenzimide (BBI), cut in half longitudinally andimaged with a 10X objective. The images were imported into MetaMorph®software for analysis. In each image, the stent tine area was traced andquantified. The cells covering the stent tine were then countedmanually. Tine area was converted into mm² using a conversion factordetermined with a standard stage microscope. The number of cells/mm² wascalculated for each image and averaged for each vessel. PEA-TEMPO-coatedstents were found to have endothelial cell coverage similar to the BMSand substantially greater than the Solef®-coated stents. The results areshown graphically in FIG. 3.

Example 3

A poly(ester-amide) topcoat was applied over a small 18 mm stent havinga poly(n-butyl methacrylate) primer and a drug reservoir layer ofpoly(vinylidene fluoride-co-hexafluoropropylene) containing 190 μg ofeverolimus. The poly(ester-amide) used was PEA-TEMPO and 89 μg wereapplied to the stent over the drug reservoir layer. The release ratetarget of the stent absent the topcoat is shown on the right in FIG. 4.The release rate obtained with the PEA-TEMPO is shown on the left. Ascan be seen, the permissible standard deviations overlap, indicatingthat the PEA-TEMPO topcoat did not detrimentally interfere with thetarget release rate.

Example 4

The effect of a poly(ester-amide) topcoat layer on the mechanicalintegrity of the stent of Example 3 was examined. A small 18 mm Vision®stent was coated with a poly(n-butyl methacrylate) primer and a drugreservoir layer of poly(vinylidene fluoride-co-hexafluoropropylene)containing 190 μg of everolimus. Over the drug reservoir layer, 89 μg ofPEA-TEMPO was spray-coated from a 2 wt % solids absolute ethanolsolution resulting in an approximately 0.92 μm thick coating of thepoly(ester-amide). The coating was then examined post-wet expansion froman overall, an outside diameter and an inside diameter perspective. Itwas found that the PEA-TEMPO coating did not introduce any observablecoating integrity failures on wet expansion.

1. An implantable medical device, comprising: a device body; an optionalprimer layer disposed over the device body; a drug reservoir layerdisposed over the device body or the primer layer, if opted, wherein thedrug reservoir layer comprises one or more therapeutic agents; anoptional rate-controlling layer disposed over at least a portion of thedrug reservoir layer, if opted; and, an optional top-coat layer disposedas an outermost layer over the device body, the primer layer, if opted,the drug reservoir layer, if opted, or the rate-limiting layer, ifopted, wherein: at least one of the layers comprises a poly(ester-amide)having the formula:[X_(m)/Y_(p)/Z_(n)]_(r)(M_(w), s, t, v) wherein: m is an integerfrom 0 to about 200; p is an integer from 0 to about 200; n is aninteger from 0 to about 200; r is an integer from 1 to about 3000; M_(n)is from about 10,000 Da to about 1,000,000 Da; s is a number from 0 to1, inclusive; t is a number from 0 to 1, inclusive; v is a number from 0to 1, inclusive; wherein:s+t+v=1; X has the chemical structure:

Y has the chemical structure:

Z has the chemical structure:

wherein: R₁, R_(1′) and R₄ are independently selected from the groupconsisting of (1C-12C)alkyl and (2C-12C)alkenyl; R₂, R_(2′), R_(2″) andR_(2′″) are independently selected from the group consisting of hydrogenand (1C-4C)alkyl, wherein: the alkyl group is optionally substitutedwith a moiety selected from the group consisting of —OH, —O(1C-4C)alkyl,—SH, —S(1C-4C)alkyl, —SeH, —COR₆, —NHC(NH)NH₂, imidazol-2-yl,imidazole-5-yl, indol-3-yl, phenyl, 4-hydroxyphenyl and4-[(1C-4C)alkylO]phenyl, wherein: R₆ is selected from the groupconsisting of —OH, —O(1C-4C)alkyl, —NH₂, —NH(1C-4C)alkyl,—N(1C-4C)alkyl₁(1C-4C)alkyl₂, a stable nitroxide,—O(CH₂)₂OP(═O)(O—)OCH₂CH₂N⁺(CH₃)₃, —O(CH₂CH₂O)_(q)CH₂CH₂OR₇ and

where: R₇ is selected from the group consisting of hydrogen,(1C-4C)alkyl, —C(O)CH═CH₂, —C(O)C(CH₃)═CH₂ and—O(CH₂)₂OP(═O)(O⁻)OCH₂CH₂N⁺(CH₃)₃; or one or more of R₂, R_(2′), R_(2″)and R_(2′″) may form a bridge between the carbon to which it is attachedand the adjacent nitrogen, the bridge comprising —CH₂CH₂CH₂—; R₃ isselected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl,(3C-8C)cycloalkyl, (3C-8C)bicycloalkyl and —(CH₂CH₂O)_(q)CH₂CH₂—; R₅ isselected from the group consisting of —CH(COR₆)CH₂S—, —CH(COR₆)CH₂O—,—CH(COR₆)(CH₂)₄NH—, —(CH₂)₄CH(COR₆)NH—, —CH(COR₆)CH(CH₃)O—

and

and, q is an integer from 1 to 600, inclusive.
 2. The implantablemedical device of claim 1, wherein M_(n) is from about 20,000 Da toabout 500,000 Da.
 3. The implantable medical device of claim 1, whereinat least an outermost layer comprises the poly(ester-amide).
 4. Theimplantable medical device of claim 3, wherein the outermost layer is atopcoat layer.
 5. The implantable medical device of claim 1, wherein: R₁is selected from the group consisting of —(CH₂)₄—, —(CH₂)₈—, and—CH₂CH═CHCH₂—; and, R_(1′) and R₄ are selected from the group consistingof —(CH₂)₄— and —(CH₂)₈—.
 6. The implantable medical device of claim 5,wherein R₂ is —CH₂CH(CH₃)₂.
 7. The implantable medical device of claim6, wherein: R₃ is —(CH₂)₆—; and, R_(3′) is


8. The implantable medical device of claim 7, wherein R₅ is—(CH₂)₄COR₆NH—, wherein: R₆ is selected from the group consisting of—O(CH₂)₂OP(═O)(O⁻)OCH₂CH₂N⁺(CH₃)₃ and —O(CH₂CH₂O)_(q)CH₂CH₂OR₇, wherein:R₇ is selected from the group consisting of hydrogen, (1C-4C)alkyl,—C(O)CH═CH₂ and —C(O)C(CH₃)═CH₂.
 9. The implantable medical device ofclaim 1, wherein p=0.
 10. The implantable medical device of claim 9,wherein R₁ and R₄ are independently selected from the group consistingof —(CH₂)₄— and —(CH₂)₈—.
 11. The implantable medical device of claim10, wherein R₂ and R₂′ are independently selected from the groupconsisting of —CH₃, —CH₂CH₂NHC(NH)NH₂, —CH₂CONH₂, —CH₂COOH, —CH₂SH,—CH₂CH₂COOH, —CH₂CH₂CONH₂, —CH₂NH₂,

—CH(CH₃)CH₂CH₃. —CH₂CH(CH₃)₂, —(CH₂)₄NH₂, (CH₂)₂SCH₃,

CH₂OH, —CH(CH₃)OH,

CH(CH₃)₂ and —CH₂CH₂CH₂—, wherein the second carbon is covalently bondedto the nitrogen adjacent to the carbon to which R₂ is bonded.
 12. Theimplantable medical device of claim 11, wherein R₃ is selected from thegroup consisting of —(CH₂)₃—, —(CH₂)₆— and —(CH₂CH₂O)_(q)CH₂CH₂—,wherein q is an integer from 1 to 10, inclusive.
 13. The implantablemedical device of claim 12, wherein R₅ is —(CH₂)₄CH(COR₆)NH—, wherein:R₆ is selected from the group consisting of a stable nitroxide,

—O(CH₂)₂OP(═O)(O—)OCH₂CH₂N⁺(CH₃)₃ and —O(CH₂CH₂O)_(q)CH₂CH₂OR₇, wherein:R₇ is selected from the group consisting of hydrogen, (1C-4C)alkyl,—C(O)CH═CH₂ and —C(O)C(CH₃)═CH₂.
 14. The implantable medical device ofclaim 12, wherein R₂ and R_(2′) are the same.
 15. The implantablemedical device of claim 14, wherein R₂ and R_(2′) are —CH₂CH(CH₃)₂. 16.The implantable medical device of claim 15, wherein the stable nitroxideis selected from the group consisting of


17. The implantable medical device of claim 16, wherein the stablenitroxide is


18. The implantable medical device of claim 15, wherein R₆ is


19. The implantable medical device of claim 1, wherein: p=0; and, n=0.20. The implantable medical device of claim 19, wherein R₂ and R₂ areselected from the group consisting of —CH₃, —H₂CH₂NHC(NH)NH₂, —CH₂CONH₂,—CH₂COOH, —CH₂SH, —CH₂CH₂COOH, —CH₂CH₂CONH₂, —CH₂NH₂,

—CH(CH₃)CH₂CH₃. —CH₂CH(CH₃)₂, —(CH₂)₄NH₂, (CH₂)₂SCH₃,

CH₂OH, —CH(CH₃)OH,

CH(CH₃)₂ and —CH₂CH₂CH₂—, wherein the second carbon is covalently bondedto the nitrogen adjacent to the carbon to which R₂ is bonded.
 21. Theimplantable medical device of claim 20, wherein R₁ is selected from thegroup consisting of —(CH₂)₄—, —(CH₂)₈— and —CH₂CH═CHCH₂—.
 22. Theimplantable medical device of claim 21, wherein R₂ and R_(2′) are thesame.
 23. The implantable medical device of claim 22, wherein R₂ andR_(2′) are CH₂CH(CH₃)₂.
 24. The implantable medical device of claim 23,wherein R₃ is selected from the group consisting of (3C-8C) alkyl,—(CH₂CH₂O)_(q)CH₂CH₂—, wherein q is an integer from 1 to 10, inclusive,

and


25. The implantable medical device of claim 23, wherein q is
 2. 26. Theimplantable medical device of claim 23, wherein R₃ is selected from thegroup consisting of —(CH₂)₃— and —(CH₂)₆—.
 27. The implantable medicaldevice of claim 23, wherein R₃ is


28. The implantable medical device of claim 26, wherein R₂ and R_(2′)are benzyl.
 29. The implantable medical device of any one of claims 1, 9or 19, comprising a drug reservoir layer and a rate-controlling layer,wherein the rate-controlling layer comprises a polymer selected from thegroup consisting of poly(L-lactide), poly(D-lactide), poly(D,L-lactide),poly(meso-lactide), poly(L-lactide-co-glycolide),poly(D-lactide.-co-glycolide), poly(D,L-lactide-co-glycolide),poly(meso-lactide-co-glycolide) and an combination thereof.
 30. Theimplantable medical device of claim 29, wherein the rate-controllinglayer comprises poly(D,L-lactide). 31 The implantable medical device ofany one of claims 1, 9 or 19, comprising a drug reservoir layer, whereinthe drug reservoir layer comprises one or more drugs disposed neat overthe primer layer.
 32. The implantable medical device of claim 1, 9 or19, comprising a drug reservoir layer, wherein the drug reservoir layercomprises one or more polymers.
 33. The implantable medical device ofclaim 32, wherein the drug is everolimus.
 34. The implantable medicaldevice of claim 33, wherein the drug reservoir layer polymer is selectedfrom the group consisting of poly(vinylidene fluoride) andpoly(vinylidene fluoride-co-hexafluoropropylene).
 35. The implantablemedical device of claim 34, further comprising a primer layer, whereinthe primer layer comprises poly(n-butyl methacrylate).
 36. Theimplantable medical device of claim 35, wherein the device is a stent.37. The implantable medical device of any one of claims 1, 9 or 19,wherein one or more of R₂, R_(2′), R_(2″), R_(2′″) and R₅ comprises apendant —COR₆ group wherein each R₆ is independently selected from thegroup consisting of a stable nitroxide entity, benzylO—,—O(CH₂)₂OP(═O)(O)CH₂CH₂N⁺(CH₃)₃ and —O(CH₂CH₂O)_(q)CH₂CH₂OR₇.
 38. Theimplantable medical device of claim 37, wherein at least an outermostlayer comprises the poly(ester-amide).
 39. The implantable medicaldevice of claim 38, wherein the outermost layer is a topcoat layer. 40.The implantable medical device of claim 37, wherein the stable nitroxideis selected from the group consisting of


41. The implantable medical device of claim 37, wherein q is 1-10,inclusive.
 42. The implantable medical device of claim 37, wherein q is300-600, inclusive.
 43. The implantable medical device of claim 37,wherein R₆ is —O(CH₂)₂OP(═O)(O)CH₂CH₂N⁺(CH₃)₃.
 44. The implantablemedical device of any one of claims 1, 9 or 19, wherein the device is astent.